PROJECT SUMMARY Cystic fibrosis (CF) is the most common lethal inherited disorder in Caucasians and affects 30,000 individuals in the United States and 70,000 individuals worldwide. Median survival now exceeds 47 years, but despite advancements in therapies and improved life expectancy, those individuals affected by CF continue to have increased morbidity and mortality. Individuals with CF have frequent pulmonary exacerbations (PEx) resulting in a decline in lung function, reduced quality of life and decreased survival. CF is a disease with equal prevalence between men and women, but women with CF have been shown to have increased mortality compared to men since the 1970s. However, the majority of data was collected prior to implementation of guidelines and novel pharmacologic therapies in this population; thus, more information is needed to identify if this disparity still exists. We hypothesize that women have increased frequency of PEx, accelerated lung function decline, slower recovery to baseline after treatment for a PEx, and decreased survival compared to men. Furthermore, it is unknown if women present with worse respiratory symptoms at onset of PEx, nor do we know if women and men are being treated differently in regards to antibiotic selection, route of antibiotics (oral versus intravenous (IV)), or duration of treatment. We propose that women present with more severe symptoms and are being treated more often with oral antibiotics and shorter duration of IV antibiotics, when prescribed, which can result in treatment failure. Finally, estrogen has been linked to PEx susceptibility in women. Further research is needed to understand the effects of hormonal variation and hormone therapy on respiratory symptoms and PEx in women with CF. We have preliminary evidence from our local cohort that women have more PEx per year compared to men. This proposal builds upon these findings by accessing data from the Cystic Fibrosis Foundation Patient Registry (CFFPR), and two multi-center trials in PEx conducted by my direct mentorship team: the Early Intervention in Cystic Fibrosis (eICE) study and the Standardized Treatment of Pulmonary Exacerbations (STOP) study. This current study will (1) evaluate a national cohort by analyzing the CFFPR to assess for current trends of frequency of PEx, lung function decline, recovery to baseline after treatment for a PEx and mortality; (2) analyze two multi-site studies (eICE and STOP) to obtain more precise information regarding sex differences in symptom presentation, provider treatment practices, and patient outcomes for a PEx; (3) leverage prospective data collected from women in our adult CF center evaluating menstrual cycle patterns, use of hormonal therapy and frequency of PEx and associated respiratory symptoms. The results of this proposal are directed at addressing public health disparities, and can impact the treatment and outcomes of women with CF worldwide. Furthermore, findings will highlight clinical presentations of PEx in women, which could lead to improvements in therapeutic management and outcomes.